Degenerative disc disease and its associated spinal disorders are common clinical problems that carry enormous socio-economic impact in today?s aging populations throughout the world. Our working hypothesis is that metabolically impaired cells in an IVD exhibiting degenerative changes or age-related changes can repair their own matrix and disc structure when exposed to growth factors, such as osteogenic protein-1 (OP-1). This hypothesis-driven proposal has several specific aims. The first is to determine if in vivo administration of growth factor can slow down or prevent IVD degeneration associated with instability. To address this aim we will (i) establish a well-controlled IVD degeneration rabbit model suitable to study disc regeneration and (ii) study, using this model, the effectiveness of intradiscally administered growth factors (i.e. OP-1) ?in counteracting the deleterious effects of spinal instability and matrix metabolic changes. Second, we propose to determine if genetically manipulated cells will over express growth factors and, when injected intradiscally, stimulate production and accumulation of matrix in IVD tissues. To address this aim we will (1) study the effects of in vitro gene-gun mediated gene transfer of growth factors (i.e. OP-1) on gene expression and matrix metabolism by human IVD cells and (ii) study the effect of an intradiscal injection of these gene-manipulated cells in rabbit model described above. Third, we will determine if tissue-engineered IVD can be formed using the alginate-recovered-chondrocyte method (ARC method). We propose to compare the abilities of IVD cells and newly-formed ARC tissue before and after they have subjected to OP-1 gene transfer. To more specifically address the potential of these approaches for the treatment of late stage IVD degeneration, we will determine if we can engineer IVD tissue suitable for transplantation using as a starting point (i) normal human IVD cells, (ii) cells that have undergone OP-1 gene transfer and (iii) cells transfected while still embedded within tissue engineered in vitro.